The Menopause Transition: Signs, Symptoms, and Management Options

Nanette Santoro; Cassandra Roeca; Brandilyn A. Peters; Genevieve Neal-Perry

Disclosures

J Clin Endocrinol Metab. 2021;106(1):1-15. 

In This Article

Physiology of the Menopausal Transition

Menopause is the final stage of ovarian physiology in women and represents a time when reproductive function is lost due to complete depletion of the finite ovarian follicle supply.[2] The menopausal transition is heralded by diminishing pool of ovarian follicles and is marked by fluctuations in reproductive hormones and changes in the menstrual pattern; often presenting with menstrual irregularities and ending with the final menstrual period (FMP). Data from prospective epidemiological studies have provided much of what we know on the hormonal changes that occur as women approach the FMP. The landmark Daily Hormone Study (DHS) of the Study of Women's Health Across the Nation (SWAN) is the only epidemiological study to collect daily urine samples across the entire menstrual cycle in women approaching the FMP,[3] providing the most complete characterization of the menopausal transition to date. This study and other prospective studies of the menopausal transition that collected daily cycle samples or early follicular phase samples, have detailed the reproductive hormone patterns and accompanying menstrual cycle and symptom patterns across the menopausal transition.[4]

Stages of the Menopausal Transition

The Stages of Reproductive Aging Workshop +10 (STRAW+10) criteria, based on menstrual bleeding patterns, represent a consensus staging system agreed upon by investigators in the field.[5] STRAW is derived from numerous worldwide studies of the menopausal transition and has clinically applicable aspects. Spanning the menopausal transition are the late reproductive stage (−3), the early menopausal transition (−2), the late menopausal transition (−1), and, following the FMP (stage 0), the early postmenopause (+1) (Figure 1). The sections below review the physiological underpinnings of these stages, including hormonal and menstrual cycle characteristics.

Figure 1.

Reproductive stages spanning the menopausal transition. Diagram of the relevant changes in menstrual cycles and hormones associated with the transition to menopause, based on the Stages of Reproductive Aging Workshop +10 (STRAW+10) criteria. Ovarian reserve is defined above as a combination of measurements: inhibin B, AMH, and ultrasound-assessed antral follicle counts.

The Late Reproductive Stage. Declines in ovarian reserve (the number of follicles remaining in the ovaries) begin prior to overt changes in menstrual cycling, with hormonal changes compensating for diminishing follicle counts to maintain regular ovulatory cycling. Anti- Müllerian hormone (AMH), produced by granulosa cells of small, growing follicles (preantral and antral follicles) before they are selected for Dominance,[6] decreases at this stage compared with in peak reproductive years,[7] likely releasing inhibition and allowing activation of the resting primordial follicle pool in an attempt to maintain ovulatory capacity.[8] AMH reaches a peak around age 25 years and then declines continuously throughout reproductive life;[9] it is reflective of the remaining primordial follicle pool from which preantral follicles are derived, making it a useful indicator of time to the FMP.[10] The level of inhibin B, produced by larger, growing follicles (antral and preovulatory follicles),[10] also becomes lower at this stage,[7] contributing to the release of negative feedback inhibition on production of FSH by the pituitary.[11] These changes are subtle and inconsistent from cycle to cycle, likely varying by the size of the growing follicle pool each month. FSH may be normal or intermittently elevated at this stage, and menstrual cycles may be normal to slightly irregular.[5]

The Early Menopausal Transition. A woman has entered the early menopausal transition when she experiences a ≥7-day difference in cycle length of consecutive menstrual Cycles.[5] However, for many women who are not tracking their menstrual cycles closely, a skipped menstrual period is the obvious first sign. Although the duration of this stage is variable, women who enter the menopausal transition at a younger age tend to have a longer duration of the early and total transition.[12] At this transition stage, the continued depletion of ovarian follicles and declines in AMH further release inhibitions on follicle activation, and follicle activation and growth are maintained in the face of dwindling follicle counts. Further declines in inhibin B alleviate negative feedback on FSH, causing it to rise earlier and at higher magnitude in the follicular phase of the menstrual cycle.[13] Follicles develop at an accelerated pace[14] and appear larger early in the cycle, but have a slower growth rate in the latter antral stage;[15] this, combined with earlier elevated FSH, results in earlier ovulation of a smaller follicle, and a shorter follicular phase.[13,15] These follicles have fewer granulosa cells,[16] however, compensatory increases in follicular aromatase activity[17] preserve estradiol levels, resulting in equal or greater estrogen levels than mid-reproductive age women.[18]

After ovulation, diminished production of progesterone and inhibin A by the corpus luteum compared with mid-reproductive aged women is observed, likely due to reduced follicle quality.[19] This reduced luteal phase feedback allows FSH to rise in the luteal phase and recruit the dominant follicle of the next menstrual cycle even prior to menses.[4] This phenomenon can manifest in a shorter subsequent menstrual cycle, with short cycles being more common in the early menopausal transition.[20] In some cycles, termed luteal-out-of-phase (LOOP) cycles, markedly high early cycle FSH leads to growth of the next cycle's dominant follicle so early in the luteal phase of the prior menstrual cycle that the next cycle's ovulation occurs concurrently or immediately after the menses of the prior cycle.[21] The out-of-phase ovulation results in very high estradiol levels, as the out-of-phase follicular estradiol is "stacked" on top of the estradiol level from the prior cycle's follicular phase. Out-of-phase ovulation results in a short menstrual cycle associated with that ovulation, however if the LOOP event was anovulatory, a long cycle could result.[21] Although the early menopausal transition is characterized by aberrant follicle growth and more variable menstrual cycles and hormone production, the majority of cycles still have evidence of luteal activity (ELA; i.e., are ovulatory cycles),[3] as defined by a rise in progesterone or its urinary metabolite, pregnanediol glucuronide (Pdg), in the luteal phase. Thus, compensatory mechanisms during the early menopausal transition (e.g., elevated FSH, increased follicular aromatase activity) are largely effective in maintaining cyclicity and fertility, albeit with some irregularity.

The Late Menopausal Transition. When a woman experiences an interval of amenorrhea ≥60 days, she has entered the late menopausal transition, which is more consistent in duration and lasts approximately 1 to 3 years.[5] At this stage, compensatory mechanisms fail and more stark changes are observed; in addition to the abnormal menstrual cycles described above, in this stage FSH is more consistently elevated, estrogen levels still fluctuate but are more consistently low, Pdg continues to decline, and cycles are less likely to demonstrate ELA (i.e., anovulatory)[3] and become longer in length.[20] Anovulatory cycles have varying underlying hormonal patterns, which have been classified as: (a) normal rise in follicular phase estrogen and normal surge of luteinizing hormone (LH), but lack of rise in luteal Pdg indicating ovulatory failure; (b) normal rise in follicular phase estrogen but failure of the LH surge, indicating hypothalamic-pituitary insensitivity to estrogen positive feedback; and (c) no rise in estrogen and no LH surge, though LH is elevated above basal levels despite premenopausal estrogen levels, believed to be due to hypothalamic-pituitary insensitivity to estrogen negative feedback.[22] There is substantial variability in these cycle types within women, such that each individual may demonstrate different anovulatory patterns as well as revert to ovulatory patterns, without clear predictability.[23] When ovulatory cycles do occur in the late menopausal transition, the cycles are of normal length and can appear hormonally normal, indicating that windows of fertility may exist up until the FMP.[3]

Early Postmenopause. Entering the early postmenopausal stage is determined retrospectively, when 12 months have passed since a woman's last menses.[5] In this stage, ovarian reserve is very low (i.e., undetectable), and FSH continues to rise while estrogen continues to fall, until they stabilize approximately 2 years after the FMP.[24]

Factors Related to the Duration and ELA Menopausal Transition Characteristics

Obesity and Body Mass Index. Higher body mass index (BMI) is related to later onset of the menopausal transition, but not its duration.[12] Obesity (BMI ≥30 kg/m2) has been associated with longer cycle lengths and lower whole-cycle urinary excretion of LH, FSH, estrone conjugates (which include estrone and estradiol), and Pdg.[3,25] Obesity is also related to relatively flattened trajectories of estradiol and FSH change across the menopausal transition.[26] The association of obesity with the probability of an ELA cycle may differ by race/ethnicity—a positive association was observed in Chinese and Japanese women, and a negative association in African American, Hispanic, and White women—but the interaction was not statistically Significant.[3]

Race/Ethnicity. African American women were shown to have longer duration of the menopausal transition than White women.[12] Additionally, the probability of ELA cycles tends to be lower in African American and Hispanic women, compared with White, Chinese, and Japanese women.[3]

Smoking. Smoking has not been associated with the probability of an ELA cycle, cycle length, or hormones,[3,25] although smoking is related to earlier entry into the menopausal transition and shorter duration of the transition.[12,27]

Central Nervous System Changes in the Menopausal Transition

Estrogen exerts feedback on the pituitary gonadotropins FSH and LH via estrogen receptors in the hypothalamus, which modulate release of gonadotropin-releasing hormone (GnRH). During the menopausal transition, the hypothalamic-pituitary axis appears to lose sensitivity to both positive and negative feedback by estrogen, resulting in anovulatory menstrual cycle patterns.[22] The hypothalamic structure of postmenopausal women has been observed to differ significantly from premenopausal women, specifically in the infundibular nucleus. Estrogen withdrawal as well as aging causes hypertrophy of a subpopulation of neurons in the infundibular nucleus expressing estrogen receptor, kisspeptin, and neurokinin B (NKB), accompanied by increased kisspeptin and NKB gene expression.[28,29] Postmenopausal women also exhibit hypertrophy of neurons in the infundibular nucleus expressing dynorphin, with reduced dynorphin gene expression, compared to premenopausal women.[30] Neurons co-expressing kisspeptin, neurokinin B, and dynorphin (KNDy neurons) are hypothesized to modulate hypothalamic gonadotropin-releasing hormone (GnRH) neurons, exerting effects on LH and FSH secretion (Figure 2);[28] although the extent of co-expression, interaction, and function of the 3 KNDy peptides appears to differ between species (e.g., rats, ruminants, nonhuman primates, and humans), as reviewed previously.[31] Notably, the co-expression and role of dynorphin in the human GnRH pulse generator remains unclear.[31] In humans, KNDy-like neurons are also thought to regulate body temperature and play a role in thermoregulation and the emergence of vasomotor symptoms (hot flashes and night sweats,[28] the hallmark manifestations of the menopausal transition. Though typically attributed to estrogen withdrawal, vasomotor symptoms begin before women become floridly and consistently hypoestrogenic and are not necessarily related to ambient estrogen or menstrual cycle patterns,[23,32,33] suggesting vasomotor symptoms may also be a manifestation of declining hypothalamic sensitivity to estrogen.[23] In the rat, KNDy neurons project to hypothalamic regions with preoptic structures that control heat dissipation, such as the median preoptic nucleus (MnPO), which express neurokinin 3 receptor (NK3R), the primary receptor for NKB.[34] Thus, increased NKB signaling from KNDy neurons to NK3R-expressing MnPO neurons is a possible neuronal pathway that may contribute to the effect of estrogen withdrawal and aging on hot flashes, although other neuronal pathways are also likely involved.[28,35] Findings in humans also support the role of NKB in hot flashes—a genome-wide association study showed that genetic variation in tachykinin receptor 3, the gene encoding NK3R, was significantly associated with hot flashes,[36] while NKB administration induces hot flashes[37] and NK3R antagonists reduce the frequency of hot flashes.[38] The projection of KNDy neurons to both heat dissipation neurons and GnRH neurons is the suspected reason for LH pulses and hot flashes occurring concurrently.[28]

Figure 2.

KNDy neuron control of GnRH secretion and hot flushes. Neurons in the hypothalamic infundibular nucleus expressing estrogen receptor, kisspeptin, neurokinin B (NKB), and possibly dynorphin (KNDy neurons) regulate GnRH neurons via kisspeptin signaling, influencing GnRH secretion and pituitary LH and FSH signaling to the ovaries. KNDy neurons may also regulate heat dissipation neurons in the median preoptic nucleus via NKB signaling. Hypertrophy and altered signaling of KNDy neurons during the menopausal transition and aging processes, as well as reduced estrogen positive and negative feedback and reduced hypothalamic sensitivity to estrogen during the menopausal transition, likely all contribute to hot flush symptoms in transitioning women.

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